ORIGINAL ARTICLES
Calcium supplementation to prevent pre-eclampsia — a
systematic review
G J Hofmeyr, A Roodt, AN Atallah, L Duley
Background. Calcium supplementation during pregnancy may
prevent high blood pressure and preterm labour.
Objective. To assess the effects of calcium supplementation
during pregnancy on hypertensive disorders of pregnancy
and related maternal and child adverse outcomes.
Design. A systematic review of randomised trials that
compared supplementation with at least 1 g calcium daily
during pregnancy with placebo.
Search strategy. The Cochrane Pregnancy and Childbirth
Group trials register (October 2001) and the Cochrane
Controlled Trials Register (Issue 3, 2001) were searched and
study authors were contacted.
Data collection and analysis. Eligibility and trial quality wer e
assessed. Data were extracted and analysed.
Main results. There was a modest reduction in the risk of preeclampsia with calcium supplementation (relative risk (RR)
0.68, 95% confidence interval (CI): 0.57- 0.81). The effect was
High blood pressure (BP) with or without proteinuria are major
causes of maternal death and morbidity worldwide,1, 2 and of
perinatal morbidity and mortality. Preterm birth, a common
association with hypertensive disorders, is the leading cause of
early neonatal death and infant mortality, particularly in lowincome countries. 3 For these reasons, strategies to reduce the
risk of hypertensive disorders of pregnancy have received
considerable attention. 4-7
During early pregnancy BP normally falls, climbing slowly
in later pregnancy to reach pre-pregnancy levels at term.8 These
normal changes in BP make the diagnosis of hypertension
during pregnancy difficult. A widely accepted definition for
hypertension is a diastolic BP (DBP) equal to or greater than 90
mmHg before the onset of labour, or an increase in systolic BP
Effective Care Research Unit, East London Hospital Complex and University of the
Witwatersrand, Johannesburg/Fort Hare University, East London, E Cape
G J Hofmeyr, MB BCh, MRCOG
A Roodt, BACur
Clinical Trials and Meta-analysis Unit, Universidade Federal de São Paulo/Escola
Paulista de Medicina, Rua Pedro de Toledo 598, São Paulo, Brazil
A N Atallah, MD
Resource Centre for Randomised Trials, Institute of Health Sciences, Old Road
Headington, Oxford, UK
L Duley, PhD
March 2003, Vol. 93, No. 3 SAMJ
greatest for women at high risk of hypertension (RR 0.21, 95%
CI: 0.11 - 0.39) and those with low baseline calcium intake
(RR 0.32, 95% CI: 0.21 - 0.49). There was no overall effect on
the risk of preterm delivery, although there was a reduction
in risk among women at high risk of hypertension (RR 0.42,
95% CI: 0.23 - 0.78). There was no evidence of any effect of
calcium supplementation on stillbirth or death before
discharge from hospital. There were fewer babies with
birthweight <2 500 g (RR 0.83, 95% CI: 0.71 - 0.98). In one
study, childhood systolic blood pressure > 95th percentile
was reduced (RR 0.59, 95% CI: 0.39 - 0.91).
Conclusions. Calcium supplementation appears to be
beneficial for women at high risk of gestational hypertension
and in communities with low dietary calcium intake. These
benefits were confined to several rather small trials, and were
not found in the largest trial to date, conducted in a low-risk
population. Further research is required.
S Afr Med J 2003; 93: 224-228.
(SBP) of 30 mmHg or more or DBP of 15 mmHg or more.
Significant proteinuria is commonly defined as 2+ by dipstick
testing, equal to or greater than 300 mg per 24 hours, or equal
to or greater than 500 mg per litre. Hypertension and
significant proteinuria occurring for the first time in the second
half of pregnancy usually indicate the presence of preeclampsia.
An inverse relationship between calcium intake and
hypertensive disorders of pregnancy was first described in
1980.9 This was based on the observation that Mayan Indians in
Guatemala, who traditionally soak their corn in lime before
cooking, had a high calcium intake and a low incidence of preeclampsia and eclampsia. A very low prevalence of preeclampsia had been reported from Ethiopia where the diet,
among other features, contained high levels of calcium.10 These
observations were supported by other epidemiological and
clinical studies, 11-14 and led to the hypothesis that an increase in
calcium intake during pregnancy might reduce the incidence of
high BP and pre-eclampsia among women with low calcium
intake.
Low calcium intake may cause high BP by stimulating either
parathyroid hormone or renin release, thereby increasing
intracellular calcium in vascular smooth muscle,12 leading to
vasoconstriction. A possible mode of action for calcium
supplementation is that it reduces parathyroid release and
ORIGINAL ARTICLES
intracellular calcium, and so reduces vascular smooth-muscle
contractility. By a similar mechanism, calcium supplementation
could also reduce uterine smooth-muscle contractility and
prevent preterm labour and delivery.15 Calcium might also have
an indirect effect on smooth-muscle function by increasing
magnesium levels.16
Calcium supplementation is attractive as a potential
intervention to reduce the risk of women developing preeclampsia. It is relatively cheap and readily available. Also, it is
likely to be safe for the woman and her child, although this
safety would need to be clearly demonstrated in pregnant
women before any attempt at widespread introduction into
clinical practice.
This hypothesis was tested in several randomised trials
commencing in the late 1980s which suggested a promising
beneficial effect for calcium supplementation. The first
systematic reviews highlighted the need for larger trials to
assess the effects on important clinical outcomes in addition to
pre-eclampsia and preterm delivery, such as perinatal
mortality. 4,17 A more recent systematic review5 came to more
enthusiastic conclusions, but this optimism was not confirmed
by a large trial in the USA.18
Objective
The objective of this systematic review was to determine, from
the best available evidence, the effect of calcium
supplementation during pregnancy on the risk of high BP and
related maternal and fetal/neonatal adverse outcomes.
Subgroup analyses were used to test whether these effects
were influenced by a low/average or high risk of hypertensive
disorders and by a low or adequate dietary calcium intake
before trial entry.
Criteria for considering studies
The Cochrane Pregnancy and Childbirth Group’s Specialised
Register of Controlled Trials and the Cochrane Controlled
Trials Register were searched to identify all published,
unpublished and ongoing trials with random allocation to
calcium supplementation during pregnancy versus placebo.
The Group searches MEDLINE and the Cochrane Controlled
Trials Register on a regular basis and reviews the contents
tables of a further 38 relevant journals received via ZETOC, an
electronic current awareness service. Relevant conference
proceedings are hand searched. There are no language
limitations. Trials with no placebo and quasi-random trials
were excluded. Trials included were those that demonstrated
an intended supplementation of at least 1 g of calcium per day
from, at the latest, 34 weeks of pregnancy compared with
placebo treatment.
The participants were pregnant women, regardless of the
March 2003, Vol. 93, No. 3 SAMJ
risk of hypertensive disorders of pregnancy. Women being
treated for hypertensive disorders of pregnancy were excluded.
Prespecified subgroups were compared as follows: (i)
women at low or average risk of hypertensive disorders of
pregnancy (unselected); (ii) women at above-average risk of
hypertensive disorders of pregnancy (this included women
selected by the trial authors on the basis of an increased risk of
hypertensive disorders of pregnancy, e.g. teenagers, women
with previous pre-eclampsia, those with an increased
sensitivity to angiotensin II and with pre-existing
hypertension); (iii) women or populations with a low baseline
dietary calcium intake (as defined by trial authors, or if not
defined, a mean intake of < 900 mg per day); and (iv) women
or populations with adequate dietary calcium intake (as
defined by trial authors, or if not defined, a mean intake equal
to or greater than 900 mg per day).
The primary outcome measures were prespecified clinical
measures as follows: For women: (i) high BPas defined by trial
authors, with or without proteinuria (pre-eclampsia plus nonproteinuric hypertension); and (ii) high BP with significant
proteinuria, as defined by trial authors (pre-eclampsia); and for
children: (i) preterm delivery (delivery before 37 weeks of
estimated gestation); (ii) birth weight < 2 500 g; (iii) admission
to a neonatal intensive care unit (NICU); and (iv) stillbirth or
death before discharge from hospital.
Eleven studies met the prestated criteria for inclusion.14,15,18,19,20-26
All were well-designed, double-blind, placebo-controlled trials.
The methodological quality appears sound but the possibility
of reporting bias must be kept in mind for those outcomes with
unreported data from some trials. In Lopez-Jaramillo et al.22 a
large discrepancy in numbers allocated to each group is not
accounted for. In some trials individual denominators were not
given for specific outcomes. Where it was clear that the
outcomes were not measured in the entire group, the
denominators were adjusted accordingly. When necessary, trial
authors were contacted for additional information.
Methods
Data were extracted from the trial reports and checked.
Descriptive data included authors, year of publication,
country, timespan of the trial, maternal age, parity, type of
placebo, baseline dietary calcium intake, type, dose, onset and
duration of calcium supplementation, compliance, cointerventions, trial quality assessments, and number
randomised and analysed.
Categorical data were compared using relative risks (RRs)
and 95% confidence intervals (CIs). Statistical heterogeneity
between trials was tested using the chi-squared test with N
(number of trials contributing data) minus 1 degree of freedom.
In the absence of significant heterogeneity ( p > 0.10) data were
pooled using a fixed effects model. If heterogeneity was
225
ORIGINAL ARTICLES
present, a random effects model was used.
For continuous data, pooled estimates of effect size were
calculated from a weighted average, with weight based on the
inverse of the variance. 27
Results
High BP with or without proteinuria
Overall there is less high BP with calcium supplementation (10
trials, 6 634 women, RR 0.81, 95% CI: 0.74 - 0.89), but there is
variation in the magnitude of the effect across the subgroups. A
funnel plot of RR against sample size showed asymmetry, with
smaller effects in the larger trials of more than 1 000 subjects.
The magnitude of the effect was considerably greater among
women at high risk of developing hypertension (4 trials, 327
women, RR 0.45, 95% CI: 0.31 - 0.66), and those with low
baseline dietary calcium (5 trials, 1 582 women; RR 0.49, 95%
CI: 0.38-0.62).
Pre-eclampsia (Figs 1 and 2)
The results follow a similar pattern to those for gestational
hypertension. The overall effect was a reduction in the risk of
pre-eclampsia (11 trials, 6 894 women; RR 0.68, 95% CI: 0.57 0.81). The effect was smallest in the largest trial which studied
low-risk women with an adequate baseline calcium diet, and
Study
Calcium
N/T
Adequate calcium diet
CPEP18
158 / 2 163
Crowther et al. 24
10 / 227
14
Villar et al.
1 / 25
Villar and Repke 15
0 / 90
Subtotal (95% CI)
169 / 2 505
Test for heterogeneity χ2 = 6.20 df = 3 p = 0.1
Test for overall effect z = 1.43 p = 0.15
Low calcium diet
Belizan et al.25
15 / 579
Lopez-Jaramillo et al. 23
2 / 55
Lopez-Jaramillo et al. 22
0 / 22
Lopez-Jaramillo et al.21
4 / 125
Purwar et al.20
2 / 97
Sanchez-Ramos et al.19
4 / 29
Subtotal (95% CI)
27 / 907
Test for heterogeneity χ 2 = 8.04 df = 5 p = 0.15
Test for overall effect z = 4.00 p = 0.00006
Total (95% CI)
196 / 3 412
Test for heterogeneity χ 2 = 28.67 df = 9 p = 0.0007
Test for overall effect z = 3.57 p = 0.0004
where the placebo group received routine low-dose calcium
supplementation.18 The results are strongly influenced by the
latter trial. The reduction is significant for women at low risk (6
trials, 6 307 women, RR 0.79, 95% CI: 0.65 - 0.94), but not those
with adequate calcium intake (4 trials, 5 022 women: RR 0.82,
95% CI: 0.71 - 1.05). Pre-eclampsia was reduced by more than
50% in women at high risk of hypertension (5 trials, 587
women: RR 0.21, 95% CI: 0.11 - 0.39), and those with low
baseline calcium intake (6 trials, 1 842 women; RR 0.32, 95%
CI: 0.21 - 0.49).
Preterm delivery
There was no overall effect, but preterm delivery was reduced
among women at high risk of developing hypertension (4
trials, 568 women, RR 0.42, 95% CI: 0.23 - 0.78).
Birth weight < 2 500 g
There were fewer babies with a birth weight of less than
2 500 g (7 trials, 6491 women; RR 0.83, 95% CI: 0.71 - 0.98). The
effect was greatest for women at high risk of hypertension (2
trials, 449 women, RR 0.45, 95% CI: 0.22 - 0.95), but this was a
post hoc subgroup analysis.
Admission to NICU
This outcome was reported in only 3 trials and no effect was
shown.
Placebo
N/T
RR
(95% CI random)
RR
(95% CI random)
168 / 2 173
23 / 229
3 / 27
3 / 88
197 / 2 517
0.94 (077, 1.16)
0.44 (0.21, 0.90)
0.36 (0.04, 3.24)
0.14 (0.01, 2.67)
0.62 (0.32, 1.20)
23 / 588
12 / 51
8 / 34
21 / 135
11 / 93
15 / 34
90 935
0.66 (0.35, 1.26)
0.15 (0.04, 0.66)
0.09 (0.01, 1.48)
0.21 (0.07, 0.58)
0.17 (0.04, 0.77)
0.31 (0.12, 0.84)
0.29 (0.16, 0.54)
287 / 3 452
0.37 (0.21, 0.64)
.1
.2
1
5
10
Fig. 1. Relative risk (RR) with 95% confidence intervals (CI), random effects model, of pre-eclampsia in women receiving calcium
supplementation compared with placebo. Subgroup analysis by baseline dietary calcium intake. (N = number with pre-eclampsia, T = total
number enrolled).
March 2003, Vol. 93, No. 3 SAMJ
ORIGINAL ARTICLES
Study
Calcium
N/T
Low-risk women
Belizan et al. 25
15 / 579
CPEP18
158 / 2 163
24
Crowther et al.
10 / 227
Lopez-Jaramillo et al.23
2 / 55
Purwar et al.20
2 / 97
Vilar et al.14
1 / 25
Subtotal (95% CI)
188 / 3 146
Test for heterogeneity χ2 = 15.10 df = 5 p = 0.0099
Test for overall effect z = 2.44 p = 0.01
High-risk women
Lopez-Jaramillo et al.22
0 / 22
Lopez-Jaramillo et al.21
4 / 125
Niromanesh et al. 26
1 / 15
Sanchez-Ramos et al.19
4 / 29
Villar and Repke 15
0 / 90
Subtotal (95% CI)
9 / 281
Test for heterogeneity χ2 = 1.23 df = 4 p = 0.87
Test for overall effect z = 4.62 p = 0.00001
Placebo
N/T
RR
(95% CI random)
RR
(95% CI random)
23 / 588
168 / 2 173
23 / 229
12 / 51
11 / 93
3 / 27
240 / 3 161
0.66 (0.35, 1.26)
0.94 (0.77, 1.16)
0.44 (0.21, 0.90)
0.15 (0.04, 0.66)
0.17 (0.04, 0.77)
0.36 (0.04, 3.24)
0.49 (0.28, 0.87)
8 / 34
21 / 135
7 / 15
15 / 34
3 / 88
54 / 306
0.09 (0.01, 1.48)
0.21 (0.07, 0.58)
0.14 (0.02, 1.02)
0.31 (0.12, 0.84)
0.14 (0.01, 2.67)
0.22 (0.12, 0.42)
Total (95% CI)
197 / 3 427
294 / 3 467
Test for heterogeneity χ2 = 31.44 df = 10 p = 0.0005
Test for overall effect z = 3.82 p = 0.0001
0.35 (0.20, 0.60)
.1
.2
1
5
10
Fig. 2. Relative risk (RR) with 95% confidence intervals (CI), random effects model, of pre-eclampsia in women receiving calcium
supplementation compared with placebo. Subgroup analysis by risk of developing pre-eclampsia (N = number with pre-eclampsia, T = total
number enrolled).
Stillbirth, or death before discharge from hospital
No effect on this outcome was shown.
Childhood hypertension
In 1 study, childhood SBP> 95th percentile was reduced in the
offspring of women who received calcium supplementation
(RR 0.59, 95% CI: 0.39 - 0.91).
Discussion
Calcium supplementation was associated with: (i) reduced
hypertension in all subgroups (although the effect was modest
for those at low risk); (ii) reduced pre-eclampsia, particularly
for those at high risk and with a low baseline dietary calcium
intake (for those with adequate calcium intake the difference
was not statistically significant); ( iii) reduced low birth weight
(for women at high risk of hypertension); (iv) reduced preterm
delivery; and (v) reduced childhood hypertension.
No side-effects of calcium supplementation have been
recorded in the trials reviewed. There is little information about
the long-term follow-up of children within these trials (with
the exception of BP assessment in 1 trial), and there is no
information about any possible changes in the use of health
March 2003, Vol. 93, No. 3 SAMJ
care resources associated with calcium supplementation.
Reduction in the risk of hypertension and pre-eclampsia may
be regarded as a meaningful outcome in itself. Women may be
distressed by these diagnoses and are commonly subjected to
more interventions and hospitalisation (although the latter was
not measured in the studies reviewed). There were, however,
no documented differences in more substantive outcomes.
The heterogeneity of results is difficult to ascribe to a
particular feature of the trials, as there is overlap between the
classification of trials according to sample size, risk of
hypertension and baseline dietary calcium intake. Most of the
included trials employed sound methodology, being doubleblind and placebo-controlled. The potential for being misled by
bias was therefore small.
Conclusions
Implications for practice
The lack of convincing evidence of effectiveness from the
largest trial to date18 may discourage the use of calcium
supplementation. It should be borne in mind that the latter trial
included women with a low risk of hypertension, an adequate
dietary calcium intake and, in addition, all women in both
227
ORIGINAL ARTICLES
groups received low-dose calcium supplementation as part of
their routine prenatal supplementation. Data from that trial are
not necessarily applicable to the care of women at greater risk
and with low dietary calcium intake.
The data included in this review support calcium
supplementation for women at high risk of gestational
hypertension, and in communities with a low dietary calcium
intake, provided that the reduction in the diagnosis of
hypertension or pre-eclampsia is regarded as important.
Whether lower dosages of calcium than used in the trials
reviewed may have similar effects cannot be determined from
this review. These benefits were confined to several rather
small trials, and were not found in the largest trial conducted
to date, in a low-risk population.
Implications for research
There is a need for a large confirmatory trial conducted in a
high-risk population. Such a trial is currently being
undertaken in several countries with demonstrated low
calcium-intake populations, including South Africa, by the
World Health Organisation, Reproductive Health and Research
Department. In preparation for the trial, dietary surveys have
been conducted at all potential sites. Nulliparous women
attending the East London Hospital Complex and Coronation
Hospital, Johannesburg, had median calcium intake below 50%
of the recommended daily allowance (Merialdi M —
unpublished data). The results of the trial will therefore be
relevant to the many South African women with inadequate
dietary calcium intake.
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